Project Summary: The overarching goal of the proposed research is to understand how skin stem cells maintain their identity when responding to cell intrinsic and extrinsic signals for self-renewal or differentiation. Self-renewal of stem cells is achieved by either symmetrical or asymmetrical cell division, through which new generations of stem cells are produced to replenish the stem cell population. However, DNA replication and cell division of adult stem cells can also lead to generation and accumulation of DNA mutations that compromise stem cell function and, in some cases, tumorigenesis. In the skin, hair follicle stem cells acquire quiescence to minimize cell turnover and division. However, it remains poorly understood how these stem cells transition between self-renewing and quiescent phases and the requirement of quiescence for long-term maintenance of stem cells. These questions have challenged investigators, because these self-renewing and quiescent stem cells are rare and usually heterogeneous in most adult tissues, making their isolation and characterization difficulty. In the skin of early adult mice, hair follicle stem cells are highly synchronized for self-renewal and quiescence. This property makes hair follicle stem cells an ideal system to investigate this fundamental question in stem cell biology. Recently, we have identified a transcription factor, Foxc1, induced in self-renewing but not quiescent hair follicle stem cells and their niche to reinforce quiescence. This finding uncovers an adaptive response of quiescent stem cells to stem cell activation during self- renewal and illuminates a path to further investigate mechanisms that control cellular state transitions in adult stem cells. In this proposal, we will utilize our innovative genomic tools and mouse models to understand adaptive control of stem cell quiescence and self-renewal mediated by transcription factors. We will first determine how multiple transcription factors regulate stem cell quiescence by coordinating transcriptional control of common and unique targets. We will determine the requirement of quiescence for long-term maintenance of hair follicle stem cells (Aim 1). We will then investigate the differences in open chromatin between self-renewing and quiescent stem cells. We will examine how the BMP signaling is controlled by transcription factors (Aim 2). Finally, we will investigate the mechanism of club hair anchorage mediated by transcription factors (Aim 3). The knowledge gained from these studies will enhance our understanding of quiescence control in hair follicle stem cells.